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3. Constitutive Activity in Angiotensin Receptors Discovery and Applications of CAM AT1R Hamiyet Unal, Ph.D. Cleveland Clinic, USA Erciyes University, Turkey Grant Support: NRSA (HU) and NIH RO1 (SK) grants, Cleveland Clinic TUBITAK Career Development Award to HU, Erciyes University

4. ARBs Renin Angiotensin System

5. Angiotensin Receptor Blockers (ARBs) Losartan: $47.3 billion (2012) Valsartan: $6.1 billion (2010) Candesartan: $17.3 billion (2011) Olmesartan: $11.2 billion (2012)

6. AngII G-protein dependent (Gq/11) G-protein independent (β-arrestin) Physiological and pathological effects of AngII Ligand-induced conformational changes in AT1R Physiological and pathological effects of AngII G-protein dependent (Gq/11) G-protein independent (β-arrestin) Therapeutic? Membrane environment Mechanical stretch Autoantibodies Mutations SNPs ARBs Therapeutic! ARBs?

7. Definition of constitutive activity Constitutive activity is the ability of a receptor to spontaneously achieve a signaling conformation, without binding an agonist. Constitutive activity is the ability of a receptor to spontaneously achieve a signaling conformation, without binding an agonist. It is also referred to as a “gain-of-function” phenotype. It is also referred to as a “gain-of-function” phenotype. The constitutively active pool of AT1R is < 5% in a cell. The constitutively active pool of AT1R is < 5% in a cell. Can constitutive activity of AT1R be increased? Can constitutive activity of AT1R be increased? Do ARBs have the ability to inhibit constitutive activity? Do ARBs have the ability to inhibit constitutive activity? Can activated AT1R be used to better understand physiology? Can activated AT1R be used to better understand physiology? Is constitutive activity of AT1R important in vivo? Is constitutive activity of AT1R important in vivo?

8. Smaller residues substituted for Asn 111 in AT1R increases constitutive activity R R* R’ R R* R’

9. Other CAMs of AT1R N111G/A/S F77Y L112H L118H L195P I245T N295A L305Q

10. Mechanism of constitutive activation in AT1R Zhang et al, 2015

11. Inverse agonism of WT and N111G-AT1R

12. Constitutive activity of native AT1R in vivo Yasuda et al, 2012

13. Pathophysiology of constitutive activity of native AT1R Agonistic autoantibodies for the human AT1 receptor are shown to lead preeclampsia and vacular allograft rejection. Zhou et al, 2008 Mechanical stress is the primary stimulus for cardiac hypertrophy due to increased afterload in vivo Yasuda et al, 2008

14. N111G-AT1R as a research tool for mimicking angiotensinergic stimulus 1.↑eNOS 2.↑NO 3.↑cGMP Reduced blood pressure

15. N111G-AT1R System wide (Liver, heart, kidney, adrenal gland, aorta) (Billet et al, 2007) ↑Blood pressure ↑Renal & cardiac fibrosis ↑Diastolic dysfunction ↓Renin & aldosterone levels ↓Baroreflex Rostral ventrolateral medulla (Allen et al, 2006) ↑Blood pressure ↑Sympathetic vasomotor tone Renal proximal tubules (Li et al, 2011) ↑Baseline blood pressure Cardiac myocytes (Ainscough et al, 2009) ↑Adverse remodeling ↑Interstitial fibrosis ↑Dilatation ↓Impaired cardiac function

16. CONCLUSIONS CAM AT1 receptors have been extremely useful and powerful in establishing local RAS activity in different tissue pathogenesis. CAM AT1 receptors have been extremely useful and powerful in establishing local RAS activity in different tissue pathogenesis. Upregulation of local AT1 receptor activity mimics various in vivo disease conditions. Upregulation of local AT1 receptor activity mimics various in vivo disease conditions. The inverse agonists are better therapeutics than neutral antagonists in treating diseases caused by constitutive activity of native GPCRs and constitutively activating mutations of GPCRs. The inverse agonists are better therapeutics than neutral antagonists in treating diseases caused by constitutive activity of native GPCRs and constitutively activating mutations of GPCRs.

17. Acknowledgements Dr. Sadashiva S. Karnik Dr. Ram Ramchandran Dr. Takanobu Takezako Dr. Zaira P. Jara Dr. Keita Noda Dr. Ying-Hong Feng Dr. Shin-ichiro Miura

18. Let us meet again.. We welcome you all to our future conferences of OMICS International 3 rd World Congress on Pharmacology On August 08-10, 2016 at Birmingham, UK http://pharmacology.pharmaceuticalconferences.com/ August 08-10, 2016 at Birmingham, UK http://pharmacology.pharmaceuticalconferences.com/ http://pharmacology.pharmaceuticalconferences.com/